Hyaluronic acid is a naturally-occurring, anionic, non-sulfated glycosaminoglycan that is distributed widely throughout connective, epithelial, and neural tissues. The average 70 kg (154 lbs) person possesses roughly 15 grams of hyaluronic acid in his/her body, one-third of which is turned over (degraded and synthesised) every day (Stern R. Eur J Cell Biol 83 (7): 317-25, (2004)). Since hyaluronic acid is found naturally in many tissues of the body and is therefore biocompatible, it is believed to be well suited for biomedical applications. Unfortunately, hyaluronic acid, when administered and used as a therapeutic in its naturally occurring form, is typically rapidly cleared from the body, making frequent administration necessary. Thus, formulations of hyaluronic acid which maintain the benefits of unaltered hyaluronic acid such as good biocompatibility, but which overcome the problem of rapid clearance are highly desirable. Such formulations should ideally have good cytocompatibility, beneficial chemical, rheological and other properties, and possess an ease of administration.
Modified forms of hyaluronic acid have been previously described. For example, hyaluronic acid having a low degree of substitution, as well as its lightly crosslinked products are described in International Patent Publication No. WO 2011/014432. The hydrogels and compositions described therein possess very low proinflammatory properties, along with several other advantageous features, but do not tend to undergo rapid gelation.
Rapid gelation is a general characteristic of in-situ forming gels. In-situ forming hydrogels are compositions that are liquid upon formation and application to a treatment site, but which undergo a phase transition to form a hydrogel thereafter. Biodegradable, injectable in-situ forming gels represent an attractive alternative to hydrogels provided as such, due to ease of administration and versatility in terms of gelation times, good adhesion, and the like.
Thus, it would be highly advantageous to form a composition possessing the advantages of the hydrogels described in International Patent Publication No. WO 2011/014432, but with the added and highly desirable benefit of being in the form of an in-situ forming gel.